Endogenous opioid peptides have been localized in the pancreatic islets in several species. We have recently demonstrated that beta-endorphin delays the clearance of an i.v. bolus of glucose in the rabbit by preventing insulin secretion. We have also shown that beta-endorphin induces a hyperglycemic state in arginine-challenged rabbits by inhibiting insulin and potentiating glucagon release. Recent in vitro studies from our laboratory indicate that beta-endorphin acts directly on the islet cells to inhibit the release of insulin. On the basis of these data, we propose the following hypothesis: (a) beta-endorphin is synthesized by the islet cells and/or peptidergic nerves of the pancreas; (b) beta-endorphin receptors are present in pancreatic islet cells; (c) beta-endorphin inhibits insulin secretion by direct action on the beta cells. This hypothesis will be tested using immunohistochemical methods and proopiomelanocortin mRNA hybridization to find evidence for the presence and local synthesis of beta-endorphin in the pancreas. Beta cells will be isolated using Percoll density gradient centrifugation, and a comparison of the relative potencies of a series of opioid agonists on glucose-stimulated insulin secretion from perifused beta cells and whole islets will be made. The potencies of agonists in the presence or absence of specific antagonists will be used as a means of receptor classification. Binding experiments using whole islets and beta cell fractions to study the characteristics of the receptor subtype, will be compared with the perifusion bioactivity data to form a profile of the pancreatic binding site. Demonstration that there is direct neuroendocrine modulation of insulin secretion is an important new concept which has major implications concerning metabolic homeostasis in a variety of physiological and pathological conditions, such as stress and diabetes.